MXPA01012783A

MXPA01012783A - Benzene derivatives, preparation method and pharmaceutical compositions containing same.

Info

Publication number: MXPA01012783A
Application number: MXPA01012783A
Authority: MX
Inventors: Robert Boigegrain
Original assignee: Sanofi Synthelabo
Priority date: 1999-06-11
Filing date: 2000-06-08
Publication date: 2002-09-18
Also published as: UA71959C2; DE60006113D1; PL352742A1; KR20020009632A; NO327778B1; YU87101A; EP1192122A1; NO20016038L; BR0011738A; CN1210250C; RS49998B; AU5539600A; AU768420B2; TWI279398B; IL146545A0; CO5180554A1; FR2794742B1; DK1192122T3; SI1192122T1; US6482986B1

Abstract

The invention concerns compounds of formula (I) wherein A, X, Y, n, R1, R2 and R3 are as defined in Claim 1. Said compounds are specifically binding to sigma receptors particularly those of the peripheral nervous system.

Description

BENZENE DERIVATIVES, METHOD OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME The present invention relates to benzene derivatives comprising an amine function substituted by an alkyl group and a cycloalkyl group, which specifically bind to the sigma receptors, especially those of the peripheral nervous system, a process for the preparation of these compounds and its use in pharmaceutical compositions and more particularly as immunosuppressants. Sigma receptors have been demonstrated by several ligands. First, opioid compounds, 6,7-benzomorpans or SKF-10,047, more particularly the chiral compound (+) SKF-10, 047 (WR Martin et al., J. Pharmacol. Exp. Ther. 1967, may be cited. 1 97, 517-532, BR Martin et al., J Pharmacol, Exp. Ther 984, 231, 539-544). I entered these compounds, the most used are the (+) N-allylmethrazocin or (+) NANM and the (+) pentazocine. A neuroleptic, haloperidol, is also a ligand for sigma receptors, as well as (+) 3- (3-hydroxyphenyl) -1-propylpiperidine or (+) 3-PPP (BLLargent et al; Proc. Nat. Acad. Sci. USA 1 984, 81, 4983-4987). The patent of US Pat. No. 4,709,094 describes highly active guanidine derivatives as ligands specific for sigma receptors; more particularly, di- (O-tolyl) guanidine or DTG can be mentioned. The anatomical distribution of the receptors in the brain has been studied by autoradiography, after labeling these receptors with the DTG, according to E. Weber et al., Proc. Nat. Acad. Sci. USA 1 986, 83, 8784-8788), as well < "Ei i-a as by the ligands (+) SKF-1 0.047 and (+) 3-PPP according to B. L. Largent et al., J. Pharmacol. Exp. Ther. USA 1986, 238, 739-748. The study by autoradiography has made it possible to clearly identify the sigma receptors of the brain and distinguish them from the other opiate receptors, as well as those of phencyclidine. Sigma receptors are particularly abundant in the central nervous system and are concentrated in the brainstem, the limbic system and the regions involved in the regulation of emotions. Sigma receptors are also found in different peripheral tissues. At least two types of sigma receptors are distinguished: sigma-1 receptors and sigma-2 receptors. Ligands of the (+) SKF-10.047 type bind selectively to sigma-1 receptors while other ligands such as DTG, haloperidol or (+) 3-PPP have a high affinity for sigma-1 receptors at the same time and sigma- 2. Patent EP 461 986 describes compounds of the formula: that are selectively linked to sigma receptors and that have an immunosuppressive activity. Among this series of compounds, [3- (3-chloro-4-cyclohexylphenyl) allyl] cyclohexylethylamine hydrochloride, (Z) of the formula: Reference may be made for example to Biological Chemistry 1997, 272 (43), 27107-271 1 5; Immunopharmacology and Immunotoxicology 1996, 18 (2), 1 79-191. The compounds of formula (A), however, possess a specific property which could be considered as a drawback. It is a property that appears during metabolism: the dependence on cytochrome called CYP 2D6. In 1957, for the first time, it was predicted that hereditary differences could be responsible for variations in response to drugs. The oxidative metabolism shows important variations according to individuals and races. Research carried out over the last 15 years has shown that variations in the functional expression of the multigenic cytochrome P450 (CYP) family are the origin of such differences. Only some isoforms of cytochrome P450 among those already characterized in man have a role in the oxidative metabolism of drugs. Reference may be made to Xenobiotica, 1986, 16, 367-378. Up to now CYPs IA2, CYP 2A6, CYP 2C9, CYP 2D6, CYP 2C9, CYP 2E1 and CYP 3A4 have been identified because of their clinical importance. Currently, it is estimated that CYP 3A4, CYP 2D6 and CYP 2C9 are responsible for themselves (and in varying degrees) of 90% of the metabolism of oxidation of medicines. Although the functional expression of these isoforms is regulated and under the influence of a large number of environmental and physiological factors, the genetic factors present the most marked influence, which underscores the important role played by the polymorphism in the oxidation of drugs. A number of polymorphisms have been studied (particularly those of CYP 2C19 and CYP 2D6). More particularly, the clinical importance of the CYP 2D6 polymorphism in the 4-hydroxylation of debrisoquine was demonstrated (Clin Pharmacol Ther, 1991, 50, 233-238). The genetic polymorphism of CYP 2D6 is responsible for the problematic metabolism of more than 30 important drugs and affects up to 10% of the Caucasian population (slow metabolizers). Now it was demonstrated that this isoform controls the biotransformation of drugs such as antiarrhythmics, β-blockers, antihypertensives, antianginals, neuroleptics and antidepressants. Apart from some exceptions, these drugs are used in psychiatric and cardiovascular medicine for long-term treatment. The pharmacokinetic consequences are mainly of a quantitative nature: the slow metabolizing subjects have a higher rate of product without change than the others. These quantitative differences have a considerable clinical impact for molecules that have a reduced therapeutic index. Therefore, genetics strongly influences differences in efficacy and side effects observed by individuals.

Thus, it is important to determine if the metabolism of a drug can be modified in case of genetic deficiency of an enzyme. Now new affinity benzene derivatives for sigma receptors, especially those of the peripheral nervous system, have been discovered according to the present invention, provided with an immunosuppressive activity but with a low metabolism rate and / or a zero or low involvement of the CYP 2D6 in the oxidation process. The compounds according to the invention also have an antitumor activity; especially inhibit the proliferation of cancer cells. On the other hand, these new compounds have shown that they have an activity from the cardiovascular point of view, with more particularity in regard to the control of heart rate. The compounds according to the invention also have an activity on apoptosis. Thus, according to one of its aspects, the present invention relates to the compounds of formula: wherein: - A represents a group selected from the following -C = C-, CH = CH, -CH2-CH2- - n is equal to 1 or 2; - X represents a hydrogen, chlorine or fluorine atom or a methyl or methoxy group; -And represents a hydrogen atom or a chlorine or fluorine atom; -Ri represents a monosubstituted cyclohexyl group, disubstituted, trisubstituted or tetrasubstituted by a methyl group; a phenyl group monosubstituted or disubstituted by a fluorine or chlorine atom or a methoxy group; a cycloheptyl, tert-butyl, dicyclopropylmethyl, bicyclo [3.2.1] octanyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl or adamantyl 1 or 2 or adamantan-2-ol group; or Ri represents a phenyl group, it being understood that in this case X and Y are different from hydrogen; -R2 represents a hydrogen atom or a (C1-C) alkyl group optionally substituted by a trifluoromethyl group; -R3 represents a (C5-C7) cycloalkyl; and the addition salts of these compounds with pharmaceutically acceptable acids, as well as their solvates and hydrates. By alkyl, is meant a monovalent hydrocarbon radical, saturated, linear or branched. By (C? -C4) alkyl, is meant an alkyl radical comprising from 1 to 4 carbon atoms. According to another of its aspects, the invention relates to the compounds of formula (1) in which: -A represents a group selected from the following: -C = C-, -CH = CH; -CH2-CH2 -n is equal to 1 or 2; -X represents a hydrogen, chlorine or fluorine atom or a methyl group ñ & ÁÁr & & ^ teá rrLk tíX ^ r & .r ^ ram.? & ££ ^ r "& -r ** £ m & & fefefe 4..m rrbm &ríZ? *. r! Sr¡m * i k, .. > ^ - ^ -r.; m & amp; & amp; amp; amp; g., methoxy; - Y represents a hydrogen atom or a chlorine or fluorine atom; -Ri represents a monosubstituted cyclohexyl group, disubstituted, trisubstituted or tetrasubstituted by a methyl group; a phenyl group monosubstituted or unsubstituted by a fluorine or chlorine atom or a methoxy group; a cycloheptyl, tert-butyl, dicyclopropylmethyl, bicyclo [3.2.l] octanyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl or adamantyl 1 or 2 group; or RT represents a phenyl group, it being understood that in this case X and Y are different from hydrogen; -R2 represents a (C? -C4) alkyl optionally substituted by a trifluoromethyl group; -R3 represents a (C5-C7) cycloalkyl; and the addition salts of these compounds with pharmaceutically acceptable acids, as well as their solvates and hydrates. According to another of its aspects, the invention relates to the compounds of the formula: in the row - A represents a group selected from the following -C = C-; -CH = CH; -CH2-CH2- - X represents a hydrogen or chlorine atom; Üaci.afc .i -. ? í ?? í í í........? . ^ r- ..

- Y represents a hydrogen atom or a chlorine atom; - R represents a monosubstituted cyclohexyl, disubstituted, trisubstituted or tetrasubstituted by a methyl group; a phenyl group substituted by a chlorine atom, a methoxy group or one or two fluorine atoms; a tertbutyl or adamantyl group 1 or 2; or RT represents a phenyl group, it being understood that in this case X and Y both represent a chlorine atom; -R2 represents a (C2-C3) alkyl; and the addition salts of these compounds with pharmaceutically acceptable acids, as well as their solvates and hydrates. According to another of its aspects, the invention relates to the compounds of formula (1) and (1 .1) in which A represents the group -CH = CH- of configuration (Z) and the addition salts of these compounds with pharmaceutically acceptable acids, as well as their solvates and hydrates. According to another of its aspects, the invention relates to the compounds as defined above, in which X represents a chlorine atom and Y represents a hydrogen or chlorine atom and the addition salts of these compounds with pharmaceutically acceptable acids, as well as their solvates and hydrates. According to another of its aspects, the invention relates to the compounds as defined above, in which Ri represents the 3,3,5,5-tetramethylcyclohexyl or 3,3-dimethylcyclohexyl or 4,4-dimethylcyclohexyl group , a phenyl group monosubstituted or disubstituted by a fluorine atom or substituted in position 4 by a chlorine atom; or an adamantyl group 1 or 2, and the addition salts of these compounds with pharmaceutically acceptable acids, as well as their solvates and hydrates. ÍÉ¡É-A * & > . & * .M.,.,.,. &3. Another aspect of the invention is constituted by the following compounds: - [(Z) -3- (4-Adamantan-2-yl-3-chlorophenyl) propen-2-yl] cyclohexylethylamine; - [(Z) -3- (4-Adamantan-2-ylphenyl) propen-2-yl] cyclohexylethylamine; -. { (Z,) -3- [4- (4,4-Diphenylcyclohexyl) -2-chlorophenyl] propen-2-yl} cyclohexylethylamine; - [(Z) -3- (4-Adamantan-l-yl-3-chlorophenyl) propen-2-yl] cyclohexylethylamine; - [(Z) -3- (4-Adamantan-2-yl-3,5-dichlorophenyl) propen-2-yl] cyclohexylethylamine; - [(Z) -3- (4-Adamantan-2-yl-3,5-dichlorophenyl) propen-2-yl] cyclohexyl (2-methylethyl) amine; as well as its salts with pharmaceutically acceptable acids, its solvates and hydrates. In particular, the invention relates to [(Z) -3- (4- Adamantan-2-yl-3,5-dichlorophenyl) propen-2-yl] cyclohexylethylamine as well as its salts with pharmaceutically acceptable acids, solvates and hydrates . The salts of the compounds according to the invention are prepared according to techniques well known to the person skilled in the art. The salts of the compounds of formula (1) according to the present invention, include those with mineral or organic acids that allow a convenient separation or crystallization of the compounds of formula (1), as well as pharmaceutically acceptable salts. As appropriate acid, mention may be made of: picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphorsulfonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, maleate, fumarate, 2-naphthalenesulfonate, paratoluenesulfonate. Among the salts of the compounds of formula (1), hydrochlorides are particularly preferred. When a compound according to the invention has one or more asymmetric carbons, the optical isomers of this compound form an integral part of the invention. When a compound according to the invention has a stereoisomerism, for example of the axial-equatorial type or Z-E type, the invention comprises all the stereoisomers of this compound. The present invention comprises the compounds of formula (1) in the form of pure isomers but also in the form of a mixture of isomers in any proportion. The compounds (I) are isolated in the form of pure isomers by the classical separation techniques: for example, fractional recrystallizations of a racemic salt with an optically active acid or base whose principle is well known or classical techniques can be used. chromatographies on chiral or non-chiral phase; for example, separation on silica gel or C18 transplanted silica can be used eluting with mixtures such as chlorinated / alcohol solvents. The compounds of formula (!) Above also include those in which one or several hydrogen, carbon or halogen atoms, especially chlorine or fluorine, have been replaced by their radioactive isotope, for example tritium or carbon -14. Such labeled compounds are useful in research work, metabolism or pharmacokinetics, in biochemical assays as receptor ligand. The functional groups optionally present in the molecule of the compounds of formula (I) and in the reactive intermediates can be protected, either permanently or temporarily, by protective groups that ensure a univocal synthesis of the expected compounds. The protection and deprotection reactions are carried out according to techniques well known to the person skilled in the art. By temporary protecting group of the amines, alcohols, phenolthiols or carboxylic acids, the protective groups are understood as described in Protective Groups in Organic Synthesis, Greene T.W. and Wuts P.G.M. , ed. John Wiley and Sons, 1 991 and in Protecting Groups, Kocienski PJ. , 1 994, Georg Thieme Verlág. The specialist will be able to select the appropriate protective groups. The compounds of formula (I) may comprise precursor groups of other functions that are subsequently generated in one or more steps. The subject of the present invention is also a process for the preparation of the compounds of formula (1), characterized in that: 1) in the case where A represents the group -C = C-; a) if n = 1, a Mannich reaction is carried out between the phenylacetylene derivative of the formula: in which Ri X and Y are as defined for (1), and formaldehyde and amine (1) HNR2R3, R2 and R3 as defined for (1); b) or a Suzuki coupling is made between the compound of the formula: wherein X, Y, n, R2 and R3 are as defined for (I) and Z represents a bromine, an iodine or trifluoromethanesulfonate group (OTf) and a boronic derivative (2) of formula R! -B (OR) 2 in which R represents a hydrogen atom, an alkyl or aryl group in the presence of a base and a metal catalyst; c) or, when R ^ represents a monosubstituted, disubstituted, trisubstituted or tetrasubstituted cyclohexyl group by a methyl group; a cycloheptyl, 4-tetrahydrothiopyranyl, 4-tetrahydropyranyl, or adamantyl group, a coupling is effected between the compound (1 a) in which Z represents an iodine or bromine atom with the ketone (3) corresponding to Ri represented by the presence of a base to obtain intermediately the compound of the formula: \ Ú? M. &? * & * T? S * -Ak im jJB = J.ajKfei A-mm *? ÑÍ? K. r ?. ,. km. Ja & M »^ ÍM. m.J.m mm? iíí? láti lÍt í? tm »i.Jl * kmm.Í? - ^ U ^ -jA in which X, Y, n, R2 and R3 are as defined for (1) then said compound (V) being reduced under selective conditions; d) or a coupling reaction is carried out between the amine of the formula: wherein n, R2 and R3 are as defined for (I) and the compound of formula " wherein Ru X and Y are as defined for (I) and Z represents a bromine atom, iodine or a trifluoromethylsulfonate group (triflate or OTf), 2) in the case where A represents the group CH = CH- , hydrogenation is carried out with nascent hydrogen or in the presence of cyclohexene of compound (1) in which A represents the acetylenic group -C = C- to prepare the ethylenic compound (1) in the form of a mixture of the Z and E isomers or this hydrogenation is carried out in the presence of a supported metal catalyst to prepare the ethylenic compound (I) in Z form or it is also reacted over the compound (1) in which IMIJ .iá-.ii.Aí, .m.ik ..,. -.,.,.,.,.,.,.,.,.,. ^ A represents the acetylenic group -C = C a metal hydride for preparing the ethylenic compound (I) in E form; 3) in the case where A represents the group -CH2-CH2-, a hydrogenation of the compound (I) is carried out in which A represents a group -CH = CH- or -C = C-. In step 1 a of the process according to the invention, the process is carried out hot, preferably at a temperature comprised between 80 and 90 ° C, in a polar solvent such as 1,2-dimethoxyethane or 1,4-dioxane. To facilitate the condensation reaction, a catalyst can be used, for example a metal salt such as copper chloride II or copper chloride ll. In step 1 b of the process, the Suzuki coupling is preferably carried out between a compound (a) in which Z represents OTf and the boronic derivative (2) of the formula R1 -B (OH) 2. The reaction is carried out in the presence of a base, such as earthy alkaline or alkaline hydroxides, alkoxides, phosphates or carbonates, more particularly potassium phosphate or sodium carbonate. The reaction is carried out in the presence of a metal catalyst, for example a catalyst of copper, tin or preferably of palladium, such as the titanium ester (triphenylphosphine) palladium, optionally with a halide of the lithium chloride type which acts as cocatalyst. It is operated hot, at a temperature comprised between 60 and 80 ° C in an inert solvent such as toluene or 1,2-dimethoxyethane or preferably in biphasic medium toluene / aqueous solution with optionally a part of alcohol such as ethanol.

The coupling of Suzuki has been studied in numerous publications, such as Synth. Commun. 1981, 11 (7), 513-519 and J. Org. Chem. 1993, 58 (8), 2201-2208. The botanical acids (2) R ^ -B (OH) 2 are commercially available or conventionally synthesized from the corresponding halogenated, preferably brominated, Ri Br derivatives by action, for example, of the trimethyl borate in the presence of a base such as ferrofuran. -butillitio. In step 1, the coupling is preferably carried out on a compound in which Z represents a bromine atom, in the presence of a base such as n-butyllithium in an inert solvent, preferably diethyl ether at low temperature, with preference being given to the temperature range from -80 to -70 ° C. The reduction of (V) in (I) is carried out under selective conditions, for example according to the method described in Tetrahedron, 1995, 51, 1143- 1 1062 by the action of chlorotrimethylsilane and sodium iodide in an acetonitrile / chlorinated solvent mixture such as dichloromethane, followed by treatment with acetic acid in the presence of zinc or also by the action of hydrous iodine or by ionic hydrogenation by the action of tetraborohydride of sodium in triflic acid. In step Id of the process, the coupling is carried out in the presence of a catalyst with palladium, one or more tertiary amines and optionally lithium chloride. It will be preferred to use a compound (II) in which Z represents a triflate and will be operated in the presence of a palladium catalyst of the titania (triphenylphosphine) palladium or dichlorodi (triphenylphosphine) palladium ester type and optionally a cocatalyst such as iodide copper. In the case where Z represents a triflate, lithium chloride will also be used. This coupling is preferably carried out in the presence of triethylamine and pyridine until the reaction mixture refluxes. For this type of coupling, called Sonogashira coupling, reference may be made to J. Org. Chem. 1993, 58, 7368-7376 and 1998, 63, 1 109-1 1 18; Syn. Lett. 1995, 1 1 1 5-1 1 16 and Synthesís, 1 987, 981. To prepare the compounds (1) in which A represents the group -CH = CH- under the form Z, hydrogenation is generally carried out in the presence of cyclohexene and a supported metal catalyst, such as palladium on barium sulfate or calcium carbonate or Raney nickel, or preferably the Lindlar catalyst, in an inert solvent for the reaction, such as petroleum ether or an alcohol solvent. To prepare the compounds (I) under Form E, it is preferred to use the metal hydride as diisobutylammonium hydride (DIBALH) in an inert solvent such as toluene. To prepare the compounds (I) in which A represents the group -CH2-CH2- , the hydrogenation is generally carried out in an alcohol, for example ethanol, in the presence of a catalyst such as platinum oxide or preferably palladium on carbon. For the techniques for reducing the alkalis and alcins used above, reference may be made to "Catalytic Hydrogenation, Techniques and Applications in Organic Chemistry," Robert L. Augustine, 1965, Marcel Dekker, Inc. New York. the compounds (1) in which A represents the acetylenic group -C = C- is described in SCHEME 1 that follows: SCHEME 1 VIA A VIA B if p if p = 1 In SCHEME 1, A = -C = C-, and X, Y, n, R,, R2 and R3 are as defined for (I), R represents a hydrogen atom, a alkyl or aryl group, Z represents a bromine, iodine or triflate atom and Z 'represents a triflate when Z represents a bromine or an iodine, if not Z' represents a bromine or iodine atom. Next, the importance of the nature of the substituents Z and Z 'in the coupling reaction described is described. D. The compound (11) is obtained by treatment in basic medium of the chloroacrolein of the formula: wherein X, Y and R ^ are as defined for (1), preferably by the action of sodium hydroxide in a solvent such as tetrahydrofuran or preferably 1,4-dioxane at the reflux temperature of the solvent. Chloroacrolein (IV) is prepared from the acetophenone of the formula: in which X, Y and Ri are as defined for (I), by action of a Vilsmeier complex. For example, chloromethylene dimethyl ammonium chloride, commercial Vilsmeier complex, or a Vilsmeier complex obtained from a disubstituted formamide is used. i? Áá.ik m *? mUVl? .. t? Mmmm .. ^? á ^ rm? .-. -J-t. m, ¿? JtjUjdtÍ ^ mm? ^ m ^)? .- ?? M l ^^ i ?? Combined with oxalyl chloride, phosphorus oxychloride or phosgene. It is generally operated in a chlorinated solvent or an ether at a temperature between -20 and 40'C. More particularly, a Vilsmeier complex obtained from dimethylformamide and oxalyl chloride in a solvent such as dichloromethane or 1,2-dimethoxyethane is used at temperatures between -10 and 10 ° C. For this type of reaction, reference may be made, for example, to J. Chem. Soc. (C) 1970, 2484-2488 and Angew. Chem. Intemat. Ed. 1963, 2, 98-99. The acetophenones (V) are known or prepared according to known methods, such as those described in Gazz. Chim. Ital. 1949, 7-9, 453-457 and J. Am. Chem. Soc. 1947, 69, 1651-1652. SCHEME 2 illustrates the methods used for the preparation of the compounds (V).

SCHEME 2 In SCHEME 2, X, Y and R are as defined for (I), Cy is as previously defined for (I "), Z represents an atom of bromine, of iodine or OTf, R represents a hydrogen atom, an alkyl or aryl group and P represents a protective group of the ketone function as a methyl. The compounds (V) can be obtained directly from the compounds (Va) by the action of the boronic compound Ri-B (OR) 2 (2) as described for the passage from (a) to (I). The ketone function of the compound (Va) can also be protected in a conventional manner, for example by the action of trialkyl orthoformate in the corresponding alcohol in the presence of an acid such as paratoluenesulfonic acid. The compound (Vp) which is reacted is thus obtained the ketone (c -y "> ^ == < under the conditions described for the passage of (a) a (I ") The ketone function is deprotected by hydrolysis in acidic medium to obtain the compound (V), said compound (V) is then reduced under the mild conditions described for the passage of (I ') (I) In certain cases, for example, when Ri represents the 4,4-dimethylcyclohexyl or 4-tetrahydropyranyl group, the compound of the formula can be formed intermediately: wherein X = O or -C (CH3) 2 will lead, after prior protection of the ketone function, hydrogenation for example in the presence of palladium on carbon in methanol, followed by deprotection of the ketone function, to the compound (V) desired.

The compounds (V) in which X and / or Y is different from hydrogen can be obtained from the compounds (V) in which X = Y = H by methods known to the person skilled in the art. For example, in the case where X and / or Y represents a chlorine atom, chlorination of the aromatic nucleus is effected by the action of chlorine gas in the presence of a Lewis acid, preferably aluminum trichloride, in a chlorinated solvent as dichloromethane, preferably OOC. The compounds (Va) are commercial or can be prepared according to methods known to the person skilled in the art. For example, in the case where Z represents a triflate, the compound (Va) can be prepared as presented in SCHEME 3: SCHEME 3 In SCHEME 3, X and Y are as defined for (1). The compounds (VIII) are commercially available or conventionally prepared. According to another of its aspects, the present invention also relates to the compounds of formula (Ia): wherein X, Y, n, R2 and R3 are as defined for (I) and Z represents a bromine, iodine or OTf atom. These compounds are new and are key intermediates in the synthesis of compounds (1) - The present invention also relates to a process for the preparation of the derivatives (la) characterized in that: - or, when n = 1, a Mannich reaction is carried out between the phenylacetylene derivative of the formula: wherein X and Y are as defined for (I) and Z represents a bromine, iodine or OTf atom, formaldehyde and amine (1) HNR2R3; - or a coupling reaction is carried out between the amine of the formula: wherein R2 R3 and n are as defined for (I) and the derivative of the formula: wherein X and Y are as defined for (1), Z represents a bromine, iodine or triflate atom and Z 'represents a bromine or iodine atom if Z represents a triflate, if not Z' represents a triflate, in the presence of a catalyst with palladium, of one or more tertiary amines and optionally of lithium chloride. The Mannich reaction is carried out under the same conditions as those described for the passage from (II) to (I). For the coupling between the compounds (MIA) and (4) a Sonogashira reaction described for the coupling of the compounds (III) and (4) is used. When Z represents a triflate and Z 'a bromine or iodine atom, it is operated in the absence of lithium chloride. On the contrary, when Z represents a bromine or iodine atom and Z 'a triflate, it is operated in the presence of lithium chloride. The use of lithium chloride allows orientation of the coupling reaction. The propargylamines (4) (where n = I) are prepared in a conventional manner, for example according to Tetrah. Lett. 1989, 30 (13), 1679-1682 from the amine (1) HNR2R3 and from 3-bromopropine by the action of potassium carbonate in acetonitrile at a temperature comprised between 50 and 80 ° C. The compounds (III) in which Z = OTf are obtained conventionally from the corresponding alcohols of the formula: ^ .¿ ... ^^^^^^^ a, ^, ^^^, ^. ^. ^. ^^^^^^^.! ^.! wherein X, Y and R are as defined for (1), by the action of trifluoromethanesulfonic anhydride (triflic anhydride) in pyridine. The alcohols (IX) are in turn obtained from the compounds of the formula: wherein Z 'represents a bromine or iodine atom according to the methods described above for the passage from (a) to (1) or from (Va) to (V). The compounds (IXa) are commercially available or prepared according to techniques well known to the person skilled in the art. The compound (lia) is prepared from the chloroacrolein of the formula: wherein X, Y are as defined for (I) and Z represents a bromine, iodine or OTf atom, in turn obtained from the acetophenone of Forums: wherein X, Y and Z are as defined above for (IVa) according to the methods described for the passage from (IV) to (II) and from (V) to (IV). The compounds according to the invention have been the subject of biochemical and pharmacological studies. The compounds of formula (I), as well as their pharmaceutically acceptable salts, hydrates and solvates, bind specifically to sigma receptors, especially those of the peripheral nervous system, also referred to as sigma-2 receptors. The affinity for sigma-1 receptors has been studied in vitro on guinea pig brain membranes, using 3 H - (+) - 3PPP as a ligand according to De Haven-Hudkins et al., Life Science 1993, 53, 41-48. The (+) pentazocine binds specifically on the sigma-I receptors. A guinea pig brain membrane fragment is prepared according to usual methods. The membrane preparation (0.3 mg protein / ml) is incubated for 1 50 minutes at 37 ° C in the presence of 0.5 nM of [3 H] - (+) - pentazocine. The non-specific binding is determined in the presence of 10 μM of (+) - pentazocine. Then they are filtered and the membranes are rinsed 3 times. The filtered matter is analyzed to determine the [3H] -pentazocin moiety specifically bound. Under these conditions, the compounds of the invention, of which are presented below examples, have CI5o comprised between 0.1 nM and 100 nM. The interaction capacity of the compounds according to the invention with sigma-2 receptors has been tested in vitro on rat spleen membranes using. as ligand for [3H] -DTG according to R. Paul et al., Journal of Neuroimmunology 1994, 52, 183-192. The membrane preparation (1 ml) is incubated with 2 nM of [3 H] -DTG for 90 minutes at 20 ° C. The amount of non-specific bonds is estimated in the presence of 10 μM of DTG or of haloperidol. The membranes are filtered, washed twice and the filtered matter is analyzed to determine the amount of [3 H] -DTG spatially bound. The compounds according to the invention have a sigma-2 activity comprised between 1 nM and 500 nM. 1. The compounds according to the invention were also tested in immunosuppressive activity tests discussed below. D-galactosamine, SEB, LPS, are from Sigma Chemical Co (St Louis, MO). The SEB contains less than 0.00029% endotoxin (proof "limulus amoebocyte lysate" Bioproduct, Walkersville, MD). These molecules are dissolved in a phosphate salt buffer solution; The compounds according to the invention are dissolved in a solution containing 5% ethanol, 5% Tween 80 and 90% water. The rats used are female Balb / C rats of 6 to 8 weeks, from the Charles River hatchery (France) and female rats C57BL / 6 and B6D2FI of 8 weeks from the IFFA CREDO hatchery (Domaines des Oncins, BP0109, 69592 L'Arbresle Cedex, France).

Determination of cytokines: 5 rats are injected with the compounds or the solvent alone, intraperitoneally 30 minutes before LPS (10 μg / rat intravenously) or orally 1 hour before. Blood samples are taken by retro-orbital or cardiac puncture, 1 hour 30 minutes after the injection of LPS. The samples are centrifuged and the serum is extracted. The serum is stored at -80 ° C before analysis. The rates of TNF-a and IL-10 are determined thanks to the ELISA series (Genzyme, Cambridge). The tests are carried out according to the instructions given in the user manual. Toxic Shock: compounds are administered to 10 animals intraperitoneally 30 minutes later, they are administered the SEB (Strapioflococcus enterotoxin B, Sigma St. Louis, MO) at the rate of 10 μg / rat intravenously, D-galactosamine (20 mg / rat, intraperitoneally). Death is confirmed 48 hours later. GVH disease (Graft-Versus-Host) or reaction of the implant against the host: the compounds to be tested or the solvent are injected only (for control) to female rats B6D2FI (H2b x H2d) intraperitoneally. 4 hours later, 7.5 x 107 mononuclear cells of rat spleen C57BL / 6 (H2b) are injected to activate the GVH. All animals are sacrificed 8 days after transplantation and the weight gain of their spleen, caused by GVH, is measured. The following index is calculated: 1 = weight of the spleen (exp) / weight of the spleen (contr) weight of the animal (exp) weight of the animal (contr) The compounds according to the invention thus exhibit, according to the results observed during these biochemical and behavioral tests, an immunosuppressive activity. 2. The compounds according to the invention were also subjected to tests demonstrating their ability to inhibit the proliferation of tumor and cancer cells. Measurement of proliferation of MDA / MB231 cells (hormone-independent breast cancer): MDA / MB231 cells are maintained in vitro by successive passages in the DMEM medium (Gibco Laboratories, Grand Island, NY) containing 10% serum fetal calf inactivated by heat, 1 mM sodium pyruvate, 100 IU / ml penicillin and 100 μg / ml streptomycin. For the measurement of proliferation, the cells, in the concentration of 2 x 105 / ml, are cultured with the products to be tested in the RPMI 1640 medium containing 10 μg / ml of bovine insulin (Sigma) and 10 μg / ml of apotransferin (Sigma), in plates 96 flat bottom reservoirs (Falcon, Becton Dickinson, Lincoln Park, NJ). Three reservoirs are made for each concentration of products to be tested. Incubation is carried out at 37 ° C in a cell culture oven (atmosphere: 95% air + 5% CO2) for 4 days. Then 2 μC of tritiated thymidine (Amersham, Les Ullis, France) is added to each reservoir to each reservoir of culture. After twenty-four hours, the cells are detached by trypsin-EDTA (Gibco) and recovered on a glass fiber filter (Filtermat A, Wallac, Turku, Finland) by means of a skatron (Pharmacia LKB, Piscataway, NJ). The radioactivity incorporated and fixed on the filter it is measured in an adapted liquid scintillation counter (Betaplate, Pharmacia LKB) 3. The compounds according to the invention were also subjected to tests demonstrating their interest in the cardiovascular field. The antiarrhythmic effects of the compounds according to the invention have been tested on reperfusion arrhythmias in the anesthetized rat. The experiment was carried out in male normo-tended rats, Sprague Dawley, with a weight of 250 to 300 g. These animals come from the IFFA CREDO hatchery. The animals are kept under standard laboratory conditions, feeding on standard foods: A04 (UAR). Water is provided ad libitum. The occlusion and reperfusion technique used in this study corresponds to the methods described by Manning et al., (Circ Res. 1984, 55, 545-548) and Kane et al. (Br. J. Pharmacol, 1984, 82, 349-357), slightly modified. The animals were anesthetized with sodium pentobarbital at 60 mg / kg intraperitoneally, tracheotomized and ventilated with ambient air (Harward respirator). A catheter (PE10) was implanted in the jugular vein for the intravenous injection of the products to be tested. Hypodermic needles were placed on the four legs of the animal to record the electrocardiogram (ECG), often Dll (Gould ESIOOO or on an Astromed 7400 polygraph). After having performed a thoracotomy, a wire was placed over the left anterior descending coronary artery, near its origin, to prepare the ligature of the artery. Both ends of the wire passed through a plastic tube located on the surface of the heart, just above the coronary artery. The occlusion of the coronary artery was performed by exerting a tension on the ends of the cable for 5 minutes, and reperfusion was performed by relaxing the tension. The temperature of the animal was controlled and maintained at 37 ° C thanks to a homeothermic coverage. For the study of the intravenous route, the products were solubilized in a mixture of PEG 400/75% distilled water and injected 5 minutes before performing the coronary ligation. The products were injected in a volume of 0.1 ml / 100 g of rat. The control group received this solvent. For the study of the oral route, the products were placed in suspension in methylcellulose at 0.6% and administered by priming in the animal in vigil, 120 minutes before performing the coronary ligation.

The products were administered in a volume of 1 ml / 1000 g of rat. The control group received this vehicle The following arrhythmias were analyzed on the ECG during the reperfusion period (study for 10 minutes), according to the Lambeth Conventions (Cardiovasc. Res., 1988, 22, 447-455): - ventricular extrasystoles (ESV) ), - ventricular tachycardia (TV), knowing that the. TV is the succession of at least four ESV, - ventricular fibrillation (VF), - and mortality due to fatal ventricular fibrillation or cardiac arrest. These arrhythmias are expressed as a percentage of animals that present the picture (frequency).

The animals were divided into groups of 4 to 10. Each animal received only one dose of product. Intravenously as well as orally, the products protect the animal from reperfusion arrhythmias by decreasing or suppressing the 5 mortality and the frequency of VF. In addition, certain products decrease and / or suppress the frequency of TV and ESV, when administered intravenously. The implication of CYP2D6 can be evidenced by in vitro metabolism studies on human hepatic microsomal fractions. The most used concept is the inhibition of the enzyme by its specific inhibitor: the quinidine used in 20 times its K, where K is the absolute value of the inhibition constant of an active principle against an enzyme. Different models allow to demonstrate, in a specific metabolic reaction, the implication of CYP2D6. - Human hepatic microsomal fractions containing the set of human hepatic isoforms incubated in the presence of an oxidoreduction cofactor (NADPH) and in the absence or presence of quinidine in 20 times their K, with respect to CYP2D6 can be used. The The decrease in metabolism observed in the presence of quinidine may be associated with the inhibition of the CYP2D6 isoform, thus proving its possible implication in the metabolic pathway (s) studied. - Microsomal fractions prepared from transfected cells expressing only one isoform of human cytochrome P-25 450 (GENTEST Corp.) can also be used.

Likewise, human hepatocytes can be used in primary culture capable of carrying out metabolic reactions of phase I and I. Incubations are then performed in kinetics 24 hours in the absence and in the presence of quinidine, a potent and specific inhibitor of CYP2D6. Reference may be made to J. Pharm. Exp. Ther. 1996, 277, 321-332. The compounds according to the invention were studied in particular in the following manner: said compound is incubated with human hepatic microsomal fractions, NADPH (oxidoreduction cofactor) as well as in the presence or absence of quinidine. The degree of inhibition of metabolism observed in the presence of quinidine reflects the implication of CYP2D6 in the metabolization of said compound. This approach is used when metabolization over hepatic microsomal fractions is of sufficient amplitude (ie greater than or equal to 10% of the amount of starting substrate). - In the case in which the metabolization of said compound on hepatic microsomes is too low to be able to quantify an inhibition with precision, or when supplementary verifications are needed, complementary, deeper studies are carried out on human hepatocytes in primary culture in kinetics. hours. The degree of involvement of CYP2D6 in the overall hepatic metabolism is then revealed by the decrease in the intrinsic clairance of said compound possibly observed in the presence of quinidine. - The results obtained show that the compounds according to the invention have a low and / or low metabolization rate »M ... ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ No signs of toxicity have been observed with these compounds in pharmacologically active doses and their toxicity is therefore compatible with their use as medicaments. The compounds of the present invention are particularly interesting and may be conveniently used as medicaments, especially for treating diseases in which it is desirable to reduce the immunological activity and also the diseases associated with inflammatory disorders. They can be cited as indicative and not restrictive: diseases with autoimmune components, such as rheumatoid polyarthritis, lupus erythematosus, diseases due to demyelination such as plaque sclerosis, Crohn's disease, at attic dermatitis, diabetes or implant rejection reactions, implant reaction against the host, organ transplant situations, or also autoimmune uveitis, uveoretinitis, BehQet disease, atherosclerosis, asthma, fibrotic diseases, idiopathic pulmonary fibrosis , cystic fibrosis, glumerulonephritis, certain spondyloarthropathies, rheumatoid spondylitis, osteoarthritis, gout, osseous and cartilaginous reabsorption, osteoporosis, Paget's disease, septic shock, sepsis, endotoxin collisions, fatigue syndrome Respiratory disease, silicosis, asbestosis, pulmonary sarcoidosis, ul colitis sedation,, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, disseminated lupus erythematosus, hemodynamic shocks, ischemic pathologies (infarction of f, -i-MfcimMiH t M «MtÉ -«? - m ^? m .. ** - *. *. ^^ - "^ '^^^^ mm Aa? myocardium, myocardial ischemia, coronary vasospasm, angina pectoris, heart failure, heart attack), post ischemic reperfusion attempts, malaria, mycobacterial infections, meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpes virus), opportunistic infections associated with AIDS, tuberculosis, psoriasis, atopic and contact dermatosis, cachexia, the damages associated with the radiations. The compounds of the invention can also be used in therapy in all the pathological processes that cause the proliferation of tumor cells. This cell proliferation can be hormone-sensitive or hormone-insensitive. More precisely, the clinical applications for which the use of these compounds can be considered comprise the diseases derived from a proliferation of tumor cells, in particular glioblastomas, neuroblastomas, lymphomas, myelomas, melanomas, leukemia, carcinomas of the colon, colorectal, epithelial, hepatic , pulmonary, mammary, ovarian, pancreatic or also of the bladder or of the prostate. The compounds according to the invention can thus be advantageously used as medicaments intended to oppose the proliferation of tumor cells, in particular as antitumor agents or anticancer agents. They may also be used in the cardiovascular field, more particularly to treat heart rhythm disorders. The compounds according to the invention can also be interesting for their neuroprotective activity, as well as for their activity on apoptosis. The use of the compounds according to the invention to treat the above-mentioned diseases, as well as for the preparation of medicaments intended to treat said diseases, forms an integral part of the invention. Therefore, the present invention also has for its object pharmaceutical compositions containing a compound according to the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof, and suitable excipients. Said excipients are selected according to the pharmaceutical form and the desired mode of administration. In the pharmaceutical compositions of the present invention, for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active ingredients of formula (I) mentioned, their salts, solvates and hydrates optionally, they can be administered in unitary forms of administration, in admixture with conventional pharmaceutical carriers, to animals and humans for the prophylaxis or treatment of the disorders or diseases mentioned. Suitable unit administration forms comprise oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal, subcutaneous administration forms, intramuscular or intravenous and forms of rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments, lotions or eye drops. In order to obtain the desired prophylactic or therapeutic effect, the dose of active ingredient may vary between 0.2 and 15 mg per kg of body weight per day. Each unit dose may contain from 10 to 300 mg, preferably from 25 to 75 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times per day so as to administer a daily dose of 10 to 1500 mg, preferably 25 to 375 mg. When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, with a cellulose derivative or with other suitable materials or they can also be treated in such a way that they have a prolonged or delayed activity and continuously release a predetermined amount of active principle. A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the obtained mixture into soft or hard capsules. A preparation in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably caloric, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate coloring Powders and granules dispersible in water may contain the active ingredient in admixture with dispersing agents or wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavoring. For a rectal administration, suppositories are used that are prepared with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible dispersants and / or wetting agents are used, for example propylene glycol or butylene glycol. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives, or with matrices such as a polymer or a cyclodextrin (patch, prolonged release forms). The compositions of the present invention may contain, beside the products of formula (I) mentioned or their pharmaceutically acceptable solvates and hydrates, other active ingredients that may be useful in the treatment of the disorders or diseases indicated above. Thus, the present invention also has for its object pharmaceutical compositions containing several active ingredients in association, among which one is a compound according to the invention. The PREPARATIONS and EXAMPLES that follow illustrate the invention without thereby limiting it. The melting points have been measured according to the Microkofler technique. Nuclear magnetic resonance spectra have been carried out in the dimethylsulfoxide unless otherwise mentioned, at 200 MHz and the chemical shifts are expressed in p.p.m. The abbreviations used hereinafter are the following: s = singlet; m = multiplet; d = doublet; t = triplet; q = quadruple Conveniently, the phenyl group of compounds (I) will be numbered hereinafter as follows: PREPARATION 1 1 -Bromo-4 (1,1-dimethoxyeti 1) benzene, compound V p (Vp): X = Y H; Z = Br; P = CH3 A mixture of 19.905 g of 1- (4-bromophenyl) ethanone, 101.4 ml of methanol, 0.22 g of para-toluenesulfonic acid hydrate and 19.9 ml of trimethylamide is stirred for 6 hours at room temperature. - lortoformate. The solution is neutralized with a 1% potassium hydroxide solution in the methanol and concentrated under reduced pressure. The oil obtained is taken up in petroleum ether, the precipitate is removed by filtration and the filtrate is evaporated under reduced pressure. Compound IVp is purified by distillation; rdt = 96%; TEb = 82 ° C (under a pressure of 0.03 mbar).

PREPARATION 2 4,4-Dimethylcyclohexanone, compound 3.1 a) 4,4-Dimethylcyclohex-2-enone To 81 ml of but-3-en-2-one and 88 ml of 2-methylpropionaldehyde in 450 ml of benzene, add to room temperature 1 ml of concentrated sulfuric acid, then the reaction mixture is heated to reflux for 13 hours to remove the water by azeotropic entrainment. After returning to room temperature, the reaction mixture is washed with an aqueous solution saturated in sodium bicarbonate, then with water. The organic phase is dried over magnesium sulfate and the solvents are evaporated under reduced pressure. After distilling, 31.1 g of the expected compound is isolated; TEb = 78 ° C (under a pressure of 22 mbar) b) 31, 1 g of 4,4-dimethylcyclohex-2-enone are hydrogenated in autoclave in 100 ml of pentane, under a pressure of 5 bar in the presence of 1, 6 g of palladium on carbon at 5%. The reaction mixture is filtered and the solvents are evaporated under reduced pressure. PREPARATION 3 4-Bromo-3,5-dichlorophenol, compound IXa.la)? / - (3,5-Dichlorophenyl) acetamide To 100 g of 3,5-dichlorophenylamine in 3000 ml of chloroform, 200 ml of water are added dropwise. pyridine, then 90 ml acetic anhydride. The reaction mixture is stirred for 12 hours at room temperature. The solvents are evaporated under reduced pressure and the residue obtained is recrystallized from 1000 ml of ethyl acetate; F = 1 82 ° C. b)? / - (4-Bromo-3,5-dichlorophenyl) acetamide i.

To 84.86 g of? / - (3,5-dichlorophenyl) acetamide and 34 g of sodium acetate in 420 ml of acetic acid, 21.3 ml of bromine diluted in 82 ml of acetic acid are added in 6 hours. . After 12 hours at room temperature, the reaction mixture is heated for 5 hours at 50 ° C. The solvents are evaporated under reduced pressure. The residue obtained is recrystallized from isopropanol; F = 224 ° C. c) 4-Bromo-3,5-dichlorophenylamine. They are stirred for 5 hours at 120 ° C and then for 12 hours at room temperature, 202 g of? / - (4-bromo-3,5-dichlorophenyl) acetamide and 220 g of sodium hydroxide (in 50% aqueous solution) in 670 ml of ethylene glycol. 3000 ml of water are added, filtered, the organic phase is dried over magnesium sulphate and the solvents are evaporated under reduced pressure. The residue obtained is crystallized in the cyclohexane; F = 132 ° C. d) Add 100 g of 4-bromo-3,5-dichlorophenylamine under stirring at 5 ° C to a mixture of 125 ml of water and 90 ml of concentrated sulfuric acid. 230 g of crushed ice are added to the reaction mixture, then 29 g of sodium nitrite in 70 ml of water and the reaction mixture is left for 15 minutes under stirring. The reaction mixture is rapidly added to a mixture composed of 280 ml of concentrated sulfuric acid and 200 ml of water brought to 160 ° C and the reaction mixture is left under stirring at 160 ° C for 1 hour. The reaction mixture is poured onto a crushed water / ice mixture and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on ~ t - - - -? "tBtflgf | 3ttaUfe.» J. mm ^ ???? ^ J ^ e mA ^ Jkmmmmlá ^ a column of silica gel eluting with a mixture "S * f. cyclohexane / dichloromethane 4/6 (v / v). H NMR: 10.5 (s, 1 H); 7.0 (s, 2H). PREPARATION 4 1 - [4- (1-Hydroxy-3,3,5,5-tetramethylcyclohexyl) phenyl] ethanone, com ponte V. 1 At -78 ° C, to a solution of 10 g of 1-bromo-4- (1,1-dimethoxyethyl) benzene (compound V p) in 100 ml of tetrahydrofuran, 27.5 ml of a 1-solution is added dropwise. , 6 M in n-butyllithium hexane. The reaction mixture is stirred for 2 hours at this temperature. A solution of 6.92 ml of 3,3,5,5-tetramethylcyclohexanone in 20 ml of tetrahydrofuran is added in 20 minutes and the reaction mixture is stirred at -78 ° C for 1 hour. After returning to room temperature, 140 ml of an aqueous solution saturated in ammonium chloride are added. Decant, extract the aqueous phase with diethyl ether, combine the organic phases, dry them over magnesium sulfate and evaporate the solvents under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane / ethyl acetate mixture, 95/5 (v / v); rdt = 88%; F = 135 ° C. In the same manner, the following compounds are prepared: 1 - [4- (Hydroxy-3,3-d-methylcyclohexyl) phenyl] ethanone, compound V.2 , fei¡? ^ M1Bt. «aaa ^» ,, J .. > ..t ...? n 1 1) m? i rñ if ^? ttí ti ^^^ '^? i? ñ iéá F = 99 ° C. 1 - [4- (Hydroxydiamantan-2-yl) phenyl] ethanone, compound V.3 i H NMR ': 7.9 (d, 2H); 7.6 (d, 2H) -, 4.8 (s, 1 H); 2.6-1.4 (m, 18H) 1 - [4- (Hydroxy-4,4-dimethylcyclohexyl) phenyl] ethanone, compound V.4 F = 88 ° C. PREPARATION 5 1 - [4-3,3,5,5-Tetramethylcyclohexyl) phenyl] ethanone, compound V.1 To a solution of 40.45 g of 1 - [4- (hydroxy-3, 3,5,5-tetramethylcyclohexyl) phenyl] ethanone (compound VM) and 56.21 g of sodium iodide in 230 ml of anhydrous acetonitrile , 38 ml, 1 ml of chlorotrimethylsilane in 45 minutes. During the addition, the temperature is maintained between 35 and 40 ° C. After 2 hours of stirring, 40 ml of acetonitrile and 39.4 ml of acetic acid are added, then 29.4 g of zinc powder are added in portions. It is heated to reflux under vigorous stirring for 4 hours.After returning to room temperature, it is filtered on celite, then washed with an aqueous solution saturated in sodium bicarbonate.The organic phase is concentrated under The pressure is reduced and the oil obtained is purified by chromatography on a column of silica gel eluting with an ethyl cyclohexane acetate mixture, 95/5 (v / v), rdt = 68%, F = 54"C. In the same manner, the following compounds are prepared: 1 - [4- (3,3-Dimethylcyclohexyl) phenyl] ethanone, compound V.2 1 H NMR: 7.8 (d, 2H); 7.2 (d, 2H); 2.7 (m, 1 H); 2.5 (s, 3H); 1, 8-1, 1 (m, 8H); 1.0 (s, 3H); 0.9 (s, 3H). 1- (4-Adamantan-2-ylphenyl) ethanone, compound V.3 F = 75 ° C PREPARATION 6 1 - [4- (4,4-Dimethylcyclohex-1-enyl) phenyl] ethanone, compound VI.1 a) l - [4- (1,1-Dimethoxyethyl) phenyl] -4,4-dimethylcyclohexanol A 1 17 g of 1-bromo-4- (1,1-dimethoxyethyl) benzene in 100 ml of tetrahydrofuran are added at -78 ° C 328 ml of a solution of 1.6 M butyl lithium in the cyclohexone and the reaction mixture is stirred for 1 hour at -78 ° C. The reactive mixture is hydrolyzed by adding crushed ice. The organic phase is decanted, dried over sodium sulfate and the solvents are evaporated under reduced pressure. The obtained compound is recrystallized from 500 ml of n-hexane; F = 88 ° C. b) Under an inert atmosphere, to 600 ml of acetonitrile, 99.32 g of 1 - [4- (1,1-dimethoxyethyl) phenyl-4,4-dimethylcyclohexanol in 300 ml of dichloromethane, 151 g of iodide of sodium and the reaction mixture is heated to 30 ° C. 102 ml of chlorotrimethylsilane chloride are added, then at 65 ° C. a mixture of 300 ml of acetonitrile and 47 ml of acetic acid is added portionwise and the reaction mixture is stirred for 12 hours at room temperature. The reaction mixture is filtered and extracted with dichloromethane. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane / ethyl acetate 99/1 (v / v) mixture. PREPARATION 7 1 - [4- (4,4-Dimethylcyclohexyl) phenyl] ethanone, compound V.4 a) 1 - (1,1-dimethoxyethyl) -4- (4,4-dimethylcyclohex-1-eneyl) benzene 36.13 g of 1- [4- (4,4-dimethylcyclohex-1-yl) phenyl] ethanone (compound VI.1) in 250 ml of methanol is stirred for 12 hours at room temperature in the presence of 0.5 g of para-toluenesulfonic acid (APTS) and 13 ml of trimethyl-orfo-formate The solvents are partially evaporated under reduced pressure. A hydroxide solution of potassium in 50% methanol, then the solvents are evaporated under reduced pressure. The residue obtained is taken up in diisopropyl ether, then the solvent is evaporated under reduced pressure. b) the compound obtained in a) in 250 ml of methanol is hydrogenated in the presence of 3 g of 5% palladium on carbon. The reaction mixture is filtered, the solvents are evaporated under reduced pressure and the residue obtained is taken up with dichloromethane. The reaction mixture is left under stirring for 1 2 hours in the presence of silica, filtered, the solvents are evaporated under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel eluting with a cyclohexane / ethyl acetate mixture. 99/1 (vlv), F = 60 ° C. PREPARATION 8 1 - [3-Chloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyl] ethanone, compound V.5 Under an inert atmosphere, at 350 ml of dichloromethane, 40.25 g of aluminum chloride are added at 0 ° C, then 5 g of 1 - [4- (3, 3,5,5-tetramethylcyclohexyl) phenyletanone (compound V. 1) in solution in dichloromethane. After 2 hours of stirring at 0 ° C, 17.1 ml of chlorine gas (d = 1.565, measured in the liquid state at -78 ° C) is bubbled into the reaction. After returning to room temperature, a water / ice mixture is added to the reaction mixture. Extract with dichloromethane, decant, dry the organic phase over magnesium sulfate and concentrate under .tt.a, a «4« «i.i * - * mfl¡, - reduced pressure. Purify on a column of silica gel eluting with a cyclohexane / dichloromethane mixture, 7/3 (v / v); rdt = 74%; F = 64 ° C. The following diclorated compounds are also isolated by chromatography: 1- [3,5-Dichloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyl] ethanone, compound V.6 1 H NMR: 7.9 (s, 1H); 7.8 (s, 1H); 3.9 (m, 1H); 2.5 (s, 3H); 2.1 (m, 2H); 1.2 (m, 4H); 1.0 (s, 6H); 0.9 (s, 6H). 1- [3,6-Dichloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyl] ethanone, compound V.7 (V.7): R, X = 3-CI; Y = 6-CI < H NMR: 7.6 (s, 1H); 7.2 (s, 1H); 3.3 (, 1H); 2.6 (s, 3H); 1.5 (m, 2H); 1.2 (m, 4H); 1.1 (s, 6H); 0.9 (s, 6H). According to the procedure described for compound V.5, the following compounds are isolated: 1- [3-Chloro-4- (3,3-dimethylcyclohexyl) phenyl] ethanone, compound V.8 iiit8AJ¿fea¿iiA.brt 1 H NMR: 7.9 (1H, s); 7.8 (d, 1H); 7.4 (d, 1H); 3.1 (m, 1H); 2.5 (s, 3H); 1.8-1.1 (m, 8H); 0.9 (s, 3H); 0.8 (s, 3H). 1- (3-Chloro-4-yeryl-butylphenyl) ethanone, compound V.9 1 H NMR: 7.8 (s, 1H); 7.7 (dJH); 7.5 (d, 1H); 2.5 (s, 3H); 1.4 (s, 9H). 1- (3,5-Chloro-4-cyclohexylphenyl) ethanone, compound V.10 1- [3-Chloro- (4,4-dimethylcyclohexyl) phenyl] ethanone, compound V.11 1 H NMR: 7.9 (s, 1H); 7.8 (d, 1H); 7.5 (dJH), 2.8 (m, 1H); 2.5 (s, 3H); 1.8-1.1 (m, 8H); 0.95 (s, 3H); 0.9 (s, 3H) PREPARATION 9 1 - [(3-Chloro-4-hydroxy) phenyl] ethanone, compound VII.L (VII.1): X = 3-CI; Y = H Under an inert atmosphere, at 63.5 ml of 2-chloro-1-methoxybenzene 8 * i% Mt * jt * j - * "~ in 500 ml of 1,2-dichloroethane, 167 g of aluminum trieloride are added, then 167 g of acetyl chloride in solution in 200 ml are added dropwise. of 1,2-dichloroethane. The reaction mixture is heated at 45 ° C for 48 hours. The reaction mixture is poured into a water / ice mixture, extracted with dichloromethane, the solvents are evaporated under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel eluting with a cyclohexane-ethyl acetate mixture, 90/1 0 (vlv) Compound VII is recrystallized. L in the cyclohexane; F = 107 ° C. PREPARATION 10 Cyclohexylethylprop-2-inylamine, compound (4.1) To 30.3 ml of cyclohexylethylamine and 29.7 g of potassium carbonate in 300 ml of acetonitrile, 20 ml of 80% 3-bromopropine are added dropwise. The reaction mixture is heated at 50 ° C for 12 hours and 6 hours at 80 ° C. It is filtered, the solvents are evaporated under reduced pressure. The compound V. 1 is purified by distillation. 1 H NMR: 3.3 (s, 2H); 3.0 (s, 1 H); 2.5 (q, 2H); 2.4 (m, 1 H); 1, 8-1, 1 (m, 1H); 1, 0 (t, 3H). In the same way, the following compounds are prepared: Cyclohexylmethylprop-2-iniamine, compound 4.2 Cyclohexylisopropylprop-2-inylamine, compound 4.3 PREPARATION 1 1 Cyclohexylethylbut-3-inylamine, compound (4.4) a) But-3-ina (4- methylphenyl) sulfonate To 36 ml of pyridine, 74.8 g of tosyl chloride are added at 80 ° C. The reaction mixture is cooled to 15 ° C, then 25 g of but- 3-in-1 -ol. The reaction mixture is stirred at room temperature for 12 hours, then 70 ml of water are added at 15 ° C, extracted with diethyl ether, then the organic phase is washed with an aqueous solution of dilute sulfuric acid, then with an aqueous solution. saturated in sodium hydrogen carbonate. The organic phase is dried over sodium sulfate and the solvents are evaporated under reduced pressure. 1 H NMR: 7.8 (d, 2H); 7.4 (d, 2H); 4.0 (t, 2H); 3.8 (s, 1 H); 2.5 (s, 3H) b) 57.9 g of the compound obtained in a) 21.7 g of sodium hydrogencarbonate, 35.7 ml of cyclohexylethylamine in 100 ml of dimethylformamide is heated to reflux for 12 hours. The reaction mixture is poured into water and extracted with diethyl ether. The organic phase is dried over magnesium sulfate and the solvents are evaporated under reduced pressure. After distilling, the expected amine is isolated; TEb = 92-94 ° C (under a pressure of 13mbar). PREPARATION 12 4-Acetyl-2-chlorophenyltrifluoromethanesulfonate, Compound Va. I (Va.1): X = 3-CI; Y = H; Z = OTf At 0 ° C, 26.7 g of 1 - [(3-chloro-4-hydroxy) phenyl] ethanone (compound Vll.1) in 700 ml of pyridine are added dropwise 26.2 ml of triflic anhydride. The reaction mixture is stirred at 0 ° C for 36 hours, the solvents are evaporated under reduced pressure and the residue is taken up in a 0.1 N solution of hydrochloric acid in dichloromethane. Decant, dry the organic phases over magnesium sulfate and evaporate the solvents under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel eluting with a mixture cyclohexa-no / ethyl acetate, 95/5 (v / v). 1 H NMR: 8.2 (s, 1 H); 8.0 (d, 1 H); 7.8 (dJ H). In the same manner, the following compounds are prepared: 4-Acetyl-2,6-dichlorophenyltrifluoromethanesulfonate, compound Va.2 (Va.2): X = 3-CI; Y = 6-CI; Z = Otf 1 H NMR: 8.2 (s, 2H); 2,6 (s, 3H) 4-Bromo-2-chlorophenyltrifluoromethanesulfonate, compound Illa. I from 4-bromo-2-chlorophenol. 1 H NMR: 8, 1 (s, 1 H); 7.7 (d, 1 H); 7.6 (dJ H). PREPARATION 13 2-Chloro-4- [3-cyclohexylethylamino) prop-1-inttjphenyltrifluoromethanesulfonate, compound la.1 Under an inert atmosphere, to 4 g of 4-bromo-3-chlorophenyltrifluoromethanesulfonate (compound 11), 0.06 g of copper iodide, 10 ml of pyridine and 20 ml of triethylamine, 2.14 g of cyclohexylethylpropionate are added. 2-inylamine (compound VII.1), then 0.41 3 g of the catalyst dichlorobiphos (triphenylphosphine) palladium VI. The reaction mixture is heated to reflux for 2 hours, then at room temperature for 12 hours. It is filtered, the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel eluting with a dichloromethane / ethanol mixture ranging from 10010 to 991 1 (v / v). The compound obtained is taken up in dichloromethane, filtered, the solvents are evaporated under reduced pressure; rdt = 76% 1 H NMR- 7.8 (s, 1 H); 7.6 (d, 1 H); 7.5 (d, 1 H); 3.6 (s, 2H); 2.6 (q, 2H); 2.4 (m, 1 H); 1, 9-1, 1 (m, 10H); 0.9 (t, 3H). PREPARATION 14 1 - [3-Chloro-4- (4-fluorophenyl) phenyl] ethanone, compound V.12 Under an inert atmosphere, 19.7 g of 4-acetyl-2-chlorophenyl-tetrafluoromethanesulfonate (compound X. 1), 10 g of 4-fluorobenzeneboronic acid, 2 g of titanium ester (triphenylphosphine) palladium are stirred at 60 ° C for 8 hours. 17.9 g of sodium carbonate in 84.5 ml of water, 591 ml of toluene, 200 ml of ethanol and 5.51 g of lithium chloride. The reaction mixture is then stirred for 12 hours at room temperature. It is filtered, the solvents of the filtrate are evaporated under reduced pressure. The obtained residue is purified by chromatography on a column of silica gel eluting with a cyclohexane / ethyl acetate mixture, 9713 (v / v); rdt = 94% 1 H NMR: 8.0 (s, 1 H); 7.9 (d, 1 H); 7.5 (m, 3H); 7.3 (m, 2H); 2.6 (s, 3H). In the same way, compounds V. 13 to V. 17 presented in TABLE 1 below are prepared.

TABLE 1 - (2-6-Dichlorobiphenyl-4-yl) ethanone, compound V.18 ^ ^ fc »l (V.18): R, = -G; X = 3-Ci; Y = 5-CI 1 H NMR: 8.0 (s, 2H); 7.4 (m, 43); 7.2 (m, 2H); 2.6 (s, 3H) 1 -. { 2,6-Dichloro-4'-fluorobiphenyl-4-yl) ethanone, compound V.19 (V.19): RT =; X = 3-CI; Y = 5-CI 1 H NMR: 8.0 (s, 2H); 7.3 (m, 4H); 2.6 (s, 3H). PREPARATION 15 3-Chloro-3- [3-chloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyl] propepa /, compound IV.1 At a temperature between -5 and 2 ° C, to a solution of 3.72 ml of dimethylformamide and 20 ml of anhydrous dichloromethane, 3.51 ml of oxalyl chloride are added dropwise, then the reaction mixture is stirred for 30 minutes at room temperature. 3,92 g of 1 - [3-chloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyl] ethanone (compound V.6) in solution in 10 ml of dichloromethane are then rapidly added, then the Reactive mixture at room temperature for 12 hours. The reaction mixture is poured into a water / ice mixture, then 20 ml of an aqueous solution of sodium ethanoate at 2.84 M are added. It is washed with 50 ml of a sodium hydrogencarbonate solution and 50 ml of water are added, the organic phase is dried over magnesium sulphate and the solvents are evaporated under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane-ethyl acetate mixture, 97/3 (v / v). 1 H NMR: 10.2 (d, 1H); 7.7 (s, 1H); 7.5 (d, 1H); 7.3 (d, 1H); 3.4 (m, 1H); 1.5 (m, 2H); 1.3 (m, 4H); 1.1 (s, 6H); 0.9 (s, 6H). In the same way, compounds IV.2 to IV.17 presented in TABLES 2 and 3 are prepared as follows: TABLE 2 PREPARATION 16 3-Chloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyletin, compound 11.1 Under an inert atmosphere and under vigorous stirring, 5.3 g of sodium hydroxide are dissolved in 150 ml of water. Add 80 ml of 1,4-dioxane and heat to reflux. 15 g of 3-chloro-3- [3-chloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyl] propene (compound IV.1) in solution in 130 ml of 1,4-dioxane are rapidly added. and the reaction mixture is maintained until reflux for 1 hour. After returning to room temperature, the reaction mixture is poured over a large volume of dichloromethane. Decant, dry the organic phase over magnesium sulfate and evaporate the solvents under reduced pressure. Purby chromatography on a column of silica gel eluting with cyclohexane; rdt = 80%. 1 H NMR:: 7.5 (s, 1 H); 7.3 (m, 2H); 4.2 (s, 1 H); 3.2 (m, 1 H); 1, 4 (m, 2H); 1, 2 (m, 4H), -1.0 (s, 6H); 0.9 (s, 6H). In the same way, compounds 11.2 to 11. 15 presented in TABLES 4 and 5 are prepared as follows: "¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿? ¿? fc :, TABLE 4 ? ^ .. to * him &? m ... > , l ^? t! ta¡íilkt ?? i ^ s ^. ^ j »Aa ^^ * jfc ^ i¿a ^ * ^ * JaJ¿ ^ jjJa ^ a ^ A% aia ^. ^ üiLl TABLE 5 PREPARATION 17 3,5-Difluorobenzeneboronic acid, compound 2.1 At 78 ° C, to 20 g of 1-bromo-3,5-fluorobenzene in 300 ml of diethyl ether, 91.5 ml of tert-butyllithium are added. The reaction mixture is stirred for 1 hour at -78 ° C, then 14.2 ml of trimethyl borate are added. The reaction mixture is stirred for 1 hour at -78 ° C, then for 12 hours at room temperature. 200 ml of a 1 N aqueous solution of hydrochloric acid are added. It is extracted with diethyl ether, the organic phase is washed with a saturated solution in sodium hydrogencarbonate, dried over magnesium sulfate and the solvents are evaporated under reduced pressure. The residue is taken up in cyclohexane and the precipitate obtained is isolated by 1 H NMR filtrate: 7.4 (m, 3H); 7.2 (m, 2H).

«J? I« «r? Tf.A. ^ Afaai« ^ a? ^^ | PREPARATION 18 4-Bromo-3-chloroacetophenone, compound Va.3 (Va.3); X = 3-CI; Y = H; Z = Br At 0 ° C, at 133.34 g of aluminum chloride in 600 ml of dichloromethane, a solution of 100 g of 4-bromoacetophenone in 250 ml of dichloromethane is added dropwise. After 2 hours of stirring at 0 ° C, 28.3 ml of previously frozen chlorine (-75 ° C) is bubbled into the medium at 0 ° C. It is stirred at room temperature for 12 hours, then the reaction mixture is hydrolyzed. Decant, extract with dichloromethane, dry the organic phases over magnesium sulfate and evaporate the solvents under reduced pressure. The residue obtained is recrystallized from hexa no; rdt = 57%; F = 80 ° C. PREPARATION 19 3-Chloro-3- (4-bromo-3-chlorophenyl) propenal, compound IVa.1 (IVa.1): X = 3-CI; Y = H; Z = Br At a temperature between 3 and 6 ° C, 15.08 ml of oxalyl chloride are added under vigorous stirring to 16 ml of dimethylformamide in 200 ml of dichloromethane. After returning to room temperature, it is stirred for 30 minutes, then a solution of 13.4 g of 4-bromo-3-chloroacetophenone (compound Va.3) in 40 ml of dichloromethane is added. The reaction mixture is stirred for 12 hours at room temperature, the reaction mixture is hydrolysed by adding a solution of 1.8 g 9 sodium acetate in 50 ml of water. After stirring for 30 minutes at room temperature, it is decanted, extracted with dichloromethane, the organic phases are dried over magnesium sulfate and The solvents are evaporated under reduced pressure. The residue obtained is recrystallized from the cyclohexane; rdt = 87%; F = 134 ° C. PREPARATION 20 [3- (4-Bromo-3-chlorophenyl) prop-2-ynyl] cyclohexylethylamine, compound la.2 (Ia-2); X H 2 CH 3 a) 1-Bromo-2-chloro-4-ethynylbenzene Under an inert atmosphere, 40 g of sodium hydroxide are dissolved in 230 ml of water, 120 ml of 1,4-dioxane are added and the reaction mixture is heated at 80 ° C. 17.5 g of 3-chloro-3- (4-bromo-3-chlorophenyl) propenal in solution are added in 400 mLl of 1,4-dioxane and the reaction mixture is stirred for 30 minutes at 80 ° C. The reaction mixture is allowed to return to room temperature, then 2300 ml of dichloromethane are added. Decant, wash the organic phase with water and dry over magnesium sulfate. The compound in solution in a dichloromethane / 1,4-dioxane mixture is used as such in the next step. b) [3- (4-Bromo-3-chlorophenyl) prop-2-inylcycloexiletilamiiia. An aqueous solution of 36% formaldehyde is added to 10.36 ml of ethylcyclohexylamine in 400 ml of 1,2-dimethoxyethane. This solution is added to the solution of the compound obtained above in the presence of 0.54 g of copper chloride II, dihydrate. The reaction mixture is stirred for 4 hours until reflux, then the reaction mixture is allowed to return to room temperature. It is filtered, the solvents are evaporated under reduced pressure, then the residue obtained is purified by chromatography on a column of silica gel, eluting with a dichloromethane / ethanol mixture, 99/1 (v / v). The obtained compound is taken up in diethyl ether and hydrochloric acid is bubbled. The precipitate obtained is filtered and dried to obtain the compound in the form of hydrochloride. 1 H NMR: 7.7 (d, 1 H); 7, β (s, 1 H); 7.2 (d, 1 H); 3.5 (s, 2H); 2.6 (q.2H); 2.4 (m, 1 H); 1, 8-1, 1 (m, 10H); 0.9 (t, 3H). PREPARATION 21 2-Chloro-4- (4,4-dimethylcyclohexyl) phenol, compound IX.1 a) 2-Chloro-4- (1-hydroxy-4,4-dimethyclohexyl) phenol A 15.1 g of 4 -bromo-2-chlorophenol in 50 ml of tetrahydrofuran, 100 ml of a solution of 1.6 n-butyllithium in hexane are added at -78 ° C, the reaction mixture is stirred for 1 hour at -78 ° C. . 10, 1 g of 4,4-dimethylcyclohexanone (compound 3J) are added and the reaction mixture is stirred again for 30 minutes at -78 ° C, then for 12 hours at room temperature. The reaction mixture is hydrolyzed with an IN hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvents are evaporated under reduced pressure. The solid obtained is purified by chromatography on a column of silica gel eluting with a cyclohexane / ethyl acetate mixture ranging from 98/2 to 90/1 0 (v / v). 1 1, 8 g of solid are obtained. 1 H NMR: 7.4 (s, 1 H); 7.2 (d, 2H) 6.9 (d, 2H); 4.5 (s, 1 H); 1, 9-1, 1 (m, 8H); 0.9 (s, 6H). b) To 11.8 g of 2-chloro-4- (1-hydroxy-4,4-dimethylcyclohexyl) phenol in 200 ml of acetic acid, 50 ml of an aqueous solution of 57% iodohydric acid are added. The reaction mixture is heated to reflux for 3 hours, the solvents are evaporated under reduced pressure. An aqueous solution of 40% sodium hydroxide, an aqueous solution of sodium carbonate, then an aqueous solution of sodium hydrogensulfate is added and extracted with diethyl ether. The organic phase is dried over magnesium sulfate and the solvents are evaporated under reduced pressure. The compound obtained is purified by chromatography on a column of silica gel, eluting with an ethyl cyclohexane / acetamate 95/5 (v / v) mixture. 1 H NMR: 9.8 (s, 1 H); 7.1 (s, 1H); 7 (d, 1H); 6.9 (d, 1H); 1.9 (m, 1H); 1.6-1.2 (m, 8H); 0.9 (s, 6H). According to the same procedure, compounds IX.2 to IX.4 are prepared: 4- (Adamantan-2-yl) -3,5-dichlorophenol, compound IX.2 obtained from compound IXa.l and adamantan- 2-one 1 H NMR: 10.1 (s, 1H); 6.8 (s, 2H); 3.4 (s, 1H); 2.4 (s, 2H); 2.3-1, 4 (m, 12H) 4- (Adamantan-2-yl) phenol, compound IX.3 1 H NMR: 9.1 (s, 1H); 7.1 (d, 2H); 6.7 (d, 2H); 2.8 (s, 1H); 2.4 (s, 2H); 1.9-1.4 (m, 12H) 4- (Adamantan-2-yl) -3-chlorophenol, compound IX.4 1 H NMR: 9.8 (s, 1H); 7.1 (s, 1H); 7.0 (d, 1H); 6.9 (d, 1H); 2.8 (s, 1H); 2.3 (m, 2H); 1.9 (m, 5H); 1.7 (m, 5H); 1.5 (m, 2H). PREPARATION 22 4- (Tetrahydropyran-4-yl) phenol, compound IX.5 a) 4- (3,6-Dihydropyran-4-yl) phenol To 12.7 g of 4-bromophenol in 150 ml of tetrahydrofuran are added at -40 ° C. At this same temperature, 100 ml of 1.6 M butyllithium are added to the reaction mixture in the hexane, then 8.1 g of 4-tetrahydropyranone. The reaction mixture is left for 18 hours at room temperature, then hydrolyzed with 1N hydrochloric acid. It is extracted several times with diethyl ether, the organic phase is dried over magnesium sulfate and the solvents are evaporated under reduced pressure. The solid obtained is purified by chromatography on a column of silica gel eluting with an ethyl cyclohexanolacetate mixture ranging from 90/10 to 80/20 (v / v). 1 H NMR: 9.4 (s, 1 H); 7.2 (d, 1 H); 6.7 (d, 1 H); 6.0 (t, 1 H); 4, 1 (d, 2H); 3.7 (t, 2H); 3.7 (t, 2H); 2.4 (t, 2H). b) 5.5 g of 4 (3,6-dihydropyran-4-yl) phenol are hydrogenated in the presence of 550 mg of 10% palladium on carbon in 100 ml of methanol for 3 hours. They are filtered, then the solvents are evaporated under reduced pressure. % NMR: 9, 1 (s, 1 H); 7 (d, 2H); 6.6 (d, 2H); 3.9 (m, 2H); 3.4 (m, 1 H); 1, 6 (m, 4H) In the same manner, the following compound is prepared: 4- (4,4-Dimethylcyclohexyl) phenol, compound IX.6 1 H NMR: 9 (s, 1 H); 7 (d, 2H); 6.7 (d, 2H); 2.2 (m, 1 H); 1, 6-1, 2 (m, 8H); 0.9 (s, 6H) PREPARATION 23 4- (Adamantan-2-yl) -3,5-difluorophenol, compound IX.7 a) 2- (2,6-difluoro-4-methoxyphenyl) adamantan-2-ol Obtained from of 4-bromo-3,5-difluorophenylmethylether in presence of an equivalent of n-butyllithium according to the procedure described in PREPARATION 22 a). b) 19 g of the product obtained in the preceding step, 200 ml of hydroiodic acid and 200 ml of acetic acid are stirred overnight at reflux temperature. After returning to room temperature, the reaction mixture is poured on a crushed ice / NaHSO3 mixture. After neutralizing with a 1N soda solution, it is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, then the solvents are evaporated under reduced pressure. PREPARATION 24 2-C loro-4- (4, 4-d imethylcyclohexyl) phenyltrif luoromethanesulfonate, compound 111.1 A 9.7 g of 2-chloro-4- (4,4-dimethylcyclohexyl) phenol (compound IX?) In 60 ml of pyridine, 8.2 ml of triflic anhydride are added at 5 ° C and the reaction mixture is left for 30 minutes at 0 ° C, then the reaction mixture is stirred at room temperature for 12 hours. The reaction mixture is hydrolyzed, then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and the solvents are evaporated under reduced pressure. The residue obtained is taken up with toluene, then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel eluting with a cyclohexane / ethyl acetate mixture ranging from 100/0 to 99/1 (v / v). 1.5 g of the compound are obtained. 1 H NMR: 7.7 (s, 1 H); 7.5 (d, 1 H); 7.4 (d, 1 H); 1, 6-1, 2 (m, 8H); 0.92 (s, 3H); 0.86 (s, 3H). íÍimí.ímÍ.i - > . r- ~ -. l! ...?: .. .. m ^, m -...._, r r ..:. '•. In accordance with the same procedure, compounds lll.2 to lll.7: 4- (Adama ntan-2-il) -3 are prepared, 5-d iclorofen i Itrif luorometansulf or nato, compound 1 (1.2 1 H NMR: 7.7 (d, 1 H); 7.6 (d, 1 H); 3.6 (m, 1 H); 3.0-1.0 (m, 14H) 4- (Admantan-2-yl) phenyltrifluoromethanesulfonate, compound 1 1 1.3 1 H NMR: 7.5 (d, 2H); 7.4 (d, 2H); 3.0 (sJ H); 2.4 (s, 2H); 1.9 (m, 5H); 1.8- 1.5 (m, 7H) 4- (Adamantan-2-yl) -3-chlorophenyltrifluoromethanesulfonate, compound 111.4 1H NMR: 7.6-7.4 (m , 3H), 3.0 (s, 1 H), 2.4 (m, 2H), 1.9 (m, 5H), 1.8-1.4 (m, 7H) 4- (Adamantan-1) -yl) phenyltrifluoromethanesulfonate, compound lll.5 1 H NMR: 7.5 (d, 2H); 7.3 (d, 2H); 2J (m, 3H); 1.8 (m, 6H); 1.7 ( m, 6H) 4- (Tetrahydropyran-4-yl) f in Itrif luoromethanesulfonate, compound 111.6 1 H NMR: 7.4 (s, 4H); 3.9 (m, 2H); 3.4 (m, 2H ); 2.8 (m, 1 H); 1.7 (m, 4H) 4- (4,4-Dimeti le iclohex il) f in i Itrif luorometansulfonate, compound 111.7 1 H NMR: 7.4-7, 3 (m, 4H), 2.6 (m, 1 H), 1, 6-1, 2 (m, 8H), 0.93 (s, 3H), 0.90 (s, 3H) The compounds of The EXAMPLES presented below are of formula (I), unless otherwise mentioned, with n = 1 and -NR2R3 = EXAMPLE 1 [3- (4-Adamantan-2-ylphenyl) prop-2-ynyl] cyclohexylethylamine hydrochloride.

To 1.1 ml, 2 ml of cyclohexylethylamine in 1000 ml of 1,2-di-ethoxyethane, 8.6 ml of 36% formaldehyde are added and the stirring is maintained at room temperature for 2 hours. This solution is added to a mixture of 16 g of 2- (4-ethynylphenyl) adamantane (compound 11.3), 0.58 g of copper chloride II, dihydrate in 400 ml of 1, 2-dimethoxyethane. The reaction mixture is heated to reflux for 2 hours, then the solvents are evaporated under reduced pressure. The obtained compound is taken up in diethyl ether and the hydrochloric acid is bubbled, filtered and the precipitate obtained is dried; F 124 ° C (HCl, 0.5 H2O). In the same way, the compounds of EXAMPLES 2 to 12 presented below are prepared. EXAMPLE 2 Hydrochloride of. { 3- [4- (3,3,5,5-tetramethylcyclohexyl) phenylprop-2-ynyl} cyclohexylethylamine.

TABLE 6 (a) 1 H NMR: 7.4 (m, 2H); 7.3 (d, 1 H); 3.6 (s, 2H); 3.4 (m, 1 H); 2.8 (m, 1 H) 2.6 (q, 2H); 1, 3-0.9 (m, 27H) EXAMPLE 12 [3- (2,6-Dichlorobiphenyl-4-yl) prop-2-ynyl] cyclohexylethylamine hydrochloride.

F = 205 ° C (HCl) EXAMPLE 13 Compound identical to that of EXAMPLE 7, but prepared differently. 3- (2-Chloro-3'-fluorobiphenyl-4-yl) prop-2-ynyl] cyclohexylethylamine hydrochloride $ t Í 7..Á ,. < O > : R.- - £ 5; X = 3-CI; Y = H; A = -C = C- Under an inert atmosphere, 3.4 g of 2-chloro-4- [3- (cyclohexylethylamino) prop-1-ynyl] phenyltrifiuoromethanesulfonate (compound: 1), 1.23 g of water are stirred under reflux for 4 hours. 3-Fluorobenzeneboronic acid 2.2 g of sodium carbonate in 10.4 ml of water, 0.68 g of lithium chloride, 75 ml of toluene, 25 ml of ethanol and 0.7 g of tetra (triphenylphosphine) palladium. It is filtered, the solvents are evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane-ethanol mixture, 99/1 (v / v). The obtained compound is taken up in diethyl ether, hydrochloric acid is bubbled. It is filtered, the solvents are evaporated under reduced pressure; F = 130 ° C (HCl, 0.2 H2O). In the same way, the compounds of EXAMPLES 14 and 15 are prepared as follows: TABLE 7 . ^^. ^ d J, EXAMPLE 16 [3- (4-Adamantan-2-yl-3-chlorophenyl) prop-2-ynylcyclohexylethylamine hydrochloride (I): R, 3-CI; Y = H; A = C = C- a) 2-. { 2-Chloro-4- [3- (cyclohexylethylamino) prop-1 -yl] phenyl} ada mantan-2-ol The [3- (4-bromo-3-chlorophenyl) propene-2-inylcyclohexylethylamine hydrochloride is treated with a 1 / V solution of sodium hydroxide in the ether to obtain the base. At -75 ° C, at 17.5 g of [3- (4-bromo-3-chlorophenyl) propene-2-ynyl] cyclohexylethylamine in 200 ml of diethyl ether, 30.5 ml of a solution of n- is added. 15% butyllithium in hexane and stirring is maintained at -75 ° C for 1 hour 30 minutes. Always at -75 ° C, 7.51 g of adamantan-2-one in 100 ml of diethyl ether are added, then the reaction mixture is stirred for 2 hours at -75 ° C. The reaction mixture is allowed to return to room temperature and stirring is maintained for 1 hour. The reactive mixture is hydrolysed, it is extracted with diethyl ether, the organic phases are dried over magnesium sulphate and the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel eluting with a dichloromethane-ethanol mixture ranging from 100/0 to 99/1 (v / v). The obtained compound is used directly in the next step. b) To 11.1 g of the compound obtained above in 50 ml of acetonitrile and 25 ml of dichloromethane, 9.78 g of sodium iodide, then 6.63 ml of chlorotrimethylsilane are added. The reaction mixture is stirred for 2 hours at 30 ° C, then 25 ml of acetonitrile, 5.12 g of zinc powder and 2.99 ml of acetic acid are added. The reaction mixture is heated at 80 ° C for 3 hours, allowed to return to room temperature, fild, washed with diethyl ether, extracted with dichloromethane, then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel eluting with a toluene / ethanol mixture 97/3 (v / v), then with a cyclohexane / ethyl acetate mixture 92.5/7.5 (v / v). The obtained compound is taken up in diethyl ether and the hydrochloride is prepared by bubbling hydrochloric acid, filng and drying the precipitate obtained; F = 1 10 ° C (HCl, 0.3 H20). EXAMPLE 17 Hydrochloride of. { 3- [4- (4,4-dimethylcyclohexyl) -2-chlorophenylprop-2-ynyl] cyclohexylethylamine . { I): R, - C = C- Under an inert atmosphere, 1.42 g of dichlorodi (triphenylphosphine) palladium is added to 8.03 g of cyclohexylethylprop-2-inylamine. (compound 4.1), 15 g of [4- (4,4-dimethylcyclohexyl) -2-chlorophenyl-trifluoromethanesulfonate (compound III.1), 0.19 g of copper iodide, 3.4 g of lithium chloride in 200 ml of triethylamine and 100 ml of pyridine. The reaction mixture is heated to reflux for 12 hours.

The solvents are evaporated under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel eluting with an ethyl cyclohexane acetate mixture ranging from 95/5 to 90/10 (v / v). The residue obtained is taken up in diethyl ether. The hydrochloride is separated by filtration, then hydrochloric acid is bubbled. The residue obtained is recrystallized from ethyl acetate. 1 H NMR: 11 (s, 1 H); 7.6-7.4 (m, 2H); 7.3 (d, 1H); 4.3 (s, 2H); 3.2 (m, 2H); 1.5 (m, 1H); 2.2-1.1 (m, 22H); 0.9 (d, 6H). In the same way, the compounds of the EXAMPLES 18 to 28 that follow. EXAMPLE 18 [4- (4-Adamantan-2-yl-2-chlorophenyl) but-3-inyl-cyclohexylethylamine hydrochloride 1 H NMR: 7.5 (d, 1H); 7.4 (s, 1H); 7.3 (d, 1H); 3.4-3.2 (m, 4H); 3.1 (m, 2H); 3.0 (s, 1H); 2.4 (s, 2H); 2.0-2.1 (m, 26H).

What is it? TABLE 8 , i. t.H, - (a) prepared according to the same synthesis scheme of EXAMPLE 1 7 using 4-bromo-3-methoxyphenol as starting maal (J.Am. Chem. Soc.1926, 48, 3129). TABLE 9 EXAMPLE 29 Hydrochloride of. { (Z) -3- [3-Chloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyl] propen-2-yl} cyclohexylethylamine.

Under an inert atmosphere and at atmospheric pressure, 3 g of the compound of EXAMPLE 3 are hydrogenated in 50 ml of petroleum ether in the presence of 3 ml of cyclohexene and 0.3 g of palladium on calcium carbonate poisoned with 3.5% lead. (Lindlar catalyst). It is fild over celite, the solvents are evaporated and the residue obtained is purified by chromatography on a column of silica gel, eluting with a dichloromethane-methanol mixture, 95/5 (v / v). The oily residue obtained is taken up in diethyl ether and hydrochloric acid is bubbled through. The precipitate is fild and dried under reduced pressure. The compound of EXAMPLE 29 is isolated in 83% yield; F = 1 58 ° C (HC1, 0.1 H 2 O). In the same way, the compounds of EXAMPLES 30 to 54 presented below are prepared: TABLE 10 TABLE 11 lint - ?? rÉi »ra ^^ A ^^ rf ^^ ifa. iiJAaAfa ^ -J "-J ^^^^ * - iS ----" - tdi ^ - ^ - - - * ". artén < You? Hft? _ «- .- * • -». < a) from the corresponding base, the fumarate salts are prepared in the following manner: 1 g of base is dissolved in 50 ml of sopropanol. It also dissolves 0.26 g of fumaric acid at 50 ° C in 100 ml of isopropanol. The solution containing the starting product is poured into the warm solution of fumaric acid. The reaction mixture is stirred for 15 minutes at room temperature, then the solvents are evaporated under reduced pressure. The obtained crystals are washed with ethyl ether, then recrystallized from acetonitrile; F = 1 58 ° C (fumarate). In the same way, the maleate is prepared: F = 166 ° C (maleate) (b) from the corresponding base, the fumarate is prepared; F = 104 ° C (fumarate) a .- * £ & to TABLE 12 (a) ES + mass: 392.4 (MH +); 251, 3 and 135.3 (b) prepared according to the same synthesis scheme of EXAMPLE 44 using compound 4.2 as starting material. EXAMPLE 53 [(Z) -3- (2,6-dichlorobiphenyl-4-yl) propen-2-yl] cyclohexylethylamine hydrochloride.

(I):, F = 120 ° C (HCl) EXAMPLE 54 [(Z) -4- (4-adamantan-2-yl-3-chlorophen-yl) buten-3-yl] -cyclohexylethylamine hydrochloride (I): Rt 2 F = 1 78 ° C (HCl). The compounds of TABLE 13 below are prepared according to the same synthesis scheme as for EXAMPLE 44: TABLE 13 ? - fH + "1" H - *** ^ ", Éü ^ hÉáriia¿feA.j (a) using 4-bromo-3-methoxyphenol as starting material (J. Am. Chem. Soc. 1926, 48, 3129) (b) using 4-bromo-2,6-dichlorophenol as starting material ( J. Am. Chem. Soc. 1933, 5501 2125-2126) EXAMPLE 64 Hydrochloride. { (E) -3-1 3-chloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyl] propen-2-yl} cyclohexylethylamine.

Under an inert atmosphere, to a solution of 4 g of the compound of EXAMPLE 4 in 40 ml of toluene, 24.3 ml of a 1 M solution of diisobutylaluminum hydride (DIBALH) in toluene are added dropwise. The reaction mixture is stirred at 40 ° C for 1 hour, then the reaction mixture is poured into a water / ice mixture and sodium hydroxide is added until a pH equal to 7. It is extracted with dichloromethane, decanted, the organic phase over magnesium sulfate and the solvents are evaporated under reduced pressure. The residue is taken up in diethyl ether, hydrochloric acid is bubbled through. The precipitate obtained is filtered and dried; F = 169 ° C (HCl, 0.2 H2O) The compounds of EXAMPLES 65 to 67 below are prepared according to the procedure described for EXAMPLE 64. EXAMPLE 65 Hydrochloride of. { (E) -3- [4- (3,3,5,5-tetramethylcyclohexyl) phenyl] propen-2-yl} cyclohexylethylamine F = 200 ° C (HCl) EXAMPLE 66 Hydrochloride of. { (E) -3- [4- (2-adamantyl) phenyl] propen-2-yl) cyclohexylethyl F = 200 ° C (HCl) EXAMPLE 67 Hydrochloride of. { (E) -3- [4- (2-Adamantyl) -3,5-dichlorophenyl] propen-2-yl} cyclohexylethylamine F = 224 ° C (HCl) EXAMPLE 68 A -AJatütÉ tA AAIP-- «-B, Hydrochloride. { 3- [3-chloro-4- (3,3,5,5-tetramethylcyclohexyl) phenyl lpropyl} cyclohexileti lam ina (0: R, = 4 g of the compound of EXAMPLE 3 are hydrogenated in the presence of 0.4 g of 10% palladium on charcoal and 50 ml of ethanol. Filter and evaporate the filtrate under reduced pressure and purify the obtained residue on a column of silica gel eluting with a toluene-ethanol mixture 97/3 (v / v). The oily residue obtained is taken up in diethyl ether, hydrochloric acid is bubbled through. The precipitate obtained is filtered and dried; F 154 ° C (HCl). In the same way, the compounds of EXAMPLES 69 to 78 presented below are prepared: TABLE 14 EXAMPLE 77 [3- (2,6-Dichlorophenyl) -4-yl) propyl] cyclohexyl ethylamine hydrochloride (?): R, = -G? = 3-C!; Y = 6-CI A = -CH2-CH2 F = 1 28 ° C (HCl) EXAMPLE 78 Hydrochloride of. { -3- [4- (2-adamantyl) -3,5-dichlorophenyl] propyl} cyclohexylethylamine (I): R CH: CH F = 220 ° C (HCl)

Claims

CLAIMS 1. Compound formula: wherein: - A represents a group selected from the following: -C = C-, CH = CH; -CH2-CH2- - n is equal to 1 or 2; - X represents a hydrogen, chlorine or fluorine atom or a methyl or methoxy group; -And represents a hydrogen atom or a chlorine or fluorine atom; -Ri represents a monosubstituted cyclohexyl group, disubstituted, trisubstituted or tetrasubstituted by a methyl group; a phenyl group monosubstituted or disubstituted by a fluorine or chlorine atom or by a methoxy group, a cycloheptyl, tert-butyl, dicyclopropylmethyl, bicyclo [3.2.1] octanyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl or adamantyl 1 or 2 group or adamantan-2-ol; or Ri represents a phenyl group, it being understood that in this case X and Y are different from hydrogen; -R2 represents a hydrogen atom or a group (C? -C4) alkyl optionally substituted by a trifluoromethyl group; -R3 represents a (C5-C) cycloalkyl, and the addition salts of these compounds with pharmaceutically acceptable acids, as well as their solvates and hydrates
2. The compounds according to claim 1, characterized in that: -A represents a group selected from the following: -C = C-, -CH = CH; -CH2-CH2 -n is equal to 1 or 2; -X represents a hydrogen, chlorine or fluorine atom or a methyl or methoxy group; - Y represents a hydrogen atom or a chlorine or fluorine atom; -Ri represents a monosubstituted cyclohexyl group, disubstituted, trisubstituted or tetrasubstituted by a methyl group; a phenyl group monosubstituted or disubstituted by a fluorine or chlorine atom or a methoxy group; a cycloheptyl, tert-butyl, dicyclopropylmethyl, bicyclo [
3.2. l] octanyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl or adamantyl 1 or 2; or R represents a phenyl group, it being understood that in this case X and Y are different from hydrogen; -R2 represents a (C? -C4) alkyl optionally substituted by a trifluoromethyl group; -R3 represents a (C5-C7) cycloalkyl; and the addition salts of these compounds with pharmaceutically acceptable acids, as well as their solvates and hydrates. 3. Compounds according to claim 1 or 2, characterized by the formula: I i-Jlií IÍMÉHI rp ti. i nti •]? f - tftfihr- mr rn- 3 - * > < * - in which: - A represents a group selected from the following: -C = C-; -CH = CH; -CH2-CH2- - X represents a hydrogen or chlorine atom; - Y represents a hydrogen atom or a chlorine atom; Ri represents a monosubstituted cyclohexyl, disubstituted, trisubstituted or tetrasubstituted by a methyl group; a phenyl group substituted by a chlorine atom, a methoxy group or one or two fluorine atoms; a tertbutyl or adamantyl group 1 or 2; or Ri represents a phenyl group, it being understood that in this case X and Y both represent a chlorine atom; -R2 represents a (C2-C3) alkyl; and the addition salts of these compounds with pharmaceutically acceptable acids, as well as their solvates and hydrates.
4. Compounds according to any of claims 1 to 3, characterized in that A represents the group -CH = CH- of configuration (Z).
5. Compounds according to any of claims 1 to 4, characterized in that X represents a chlorine atom and Y represents a hydrogen or chlorine atom.
6. Compounds according to any of claims 1 to 5, characterized in that Ri represents the group 3, 3,5,5-tetramethylcyclohexyl or 3,3-dimethylcyclohexyl or 4,4-dimethylcyclohexyl, a phenyl group monosubstituted or disubstituted by a fluorine atom or substituted in the 4-position by an atom of chlorine; or an adamantyl group 1 or 2.
7. Compounds according to claim 1 characterized in that they are selected from: - [(Z) -3- (4-Adamantan-2-yl-3-chlorophenyl) propen-2-yl] cyclohexylethylamine; - [(Z) -3- (4-Adama nta n-2-ylphenyl) propen-2-yl] cyclohexylethyl mine; -. { (Z,) - 3- [4- (4,4-D-methylcyclohexyl) -2-chlorophenyl] propen-2-yl} cyclohexylethylamine; - [(Z) -3- (4-Adamantan-l-yl-3-chlorophenyl) propen-2-yl] cyclohexylethylamine; - [(Z) -3- (4-Adamantan-2-y1-3, 5-d-chlorofenyl) propen-2-yl] cyclohexylethyl mine; - [(Z) -3- (4-Ada blanket n-2-i 1-3, 5-d-chloro-phenol-yl) propen-2-yl] -cyclohexyl (2-methylethyl) -amine; as well as its salts with pharmaceutically acceptable acids, its solvates and hydrates.
8. [(Z) -3- (4-Adamantan-2-yl-3,5-dichlorophenyl) propene-2-yl cyclohexylethylamine as well as its salts with pharmaceutically acceptable acids, solvates and hydrates according to claim 7.
9. Process for the preparation of a compound according to claim 1, wherein A represents the group -C = C- characterized in that: a) if n = 1, a Mannich reaction is carried out between the phenylacetylene derivative of the formula: - wherein Ri X and Y are as defined for (1), and formaldehyde and amine (1) HNR2R3, R2 and R3 as defined for (1); b) or a Suzuki coupling is made between the compound of the formula: wherein X, Y, n, R2 and R3 are as defined for (I) and Z represents a bromine, an iodine or trifluoromethanesulfonate group (OTf) and a boronic derivative (2) of formula R? -B (OR) 2 in which R represents a hydrogen atom, an alkyl or aryl group in the presence of a base and a metal catalyst; c) or, when R1 represents a monosubstituted, disubstituted, trisubstituted or tetrasubstituted cyclohexyl group by a methyl group; a cycloheptyl, 4-tetrahydrothiopyranyl, 4-tetrahydropyranyl, or adamantyl group, a coupling is effected between the compound (1 a) in which Z represents an iodine or bromine atom with the ketone (3) corresponding to Ri (§T > == o represented p> oorr ^ N * - - ^^ e in the presence of a base to obtain intermediately the compound of formula in which X, Y, n, R2 and R3 are as defined for (1) ) said compound (Y) is then reduced under selective conditions, d) or a coupling reaction between the amine of the formula is carried out: R / 2 H-C = C- '(CH2) - N \ (4) R wherein n, R2 and R3 are as defined for (I) and the compound of formula wherein R, X and Y are as defined for (I) and Z represents a bromine atom, iodine or a trifluoromethylsulfonate group (triflate or OTf);
10. Process for the preparation of a compound according to claim 1, in which A represents the group CH = CH-characterized in that hydrogenation is carried out with nascent hydrogen or in the presence of cyclohexene of the compound (I) in which A represents the acetylenic group -C = C- to prepare the ethylenic compound (I) in the form of a mixture of the Z and E isomers or this hydrogenation is carried out in the presence of a supported metal catalyst to prepare the ethylenic compound (I) in the Z form or it is also reacted on the compound (I) in which A represents the acetylenic group -C = C- a metal hydride to prepare the ethylenic compound (I) in the form of E 1 1. Process for the preparation of a compound according to claim 1, in which A represents the group -CH 2 -CH 2 - characterized in that a hydrogenation of the compound (1) is carried out in which A represents a group -CH = CH- or -C = C-. 12. Pharmaceutical composition characterized in that it contains as the active principle a compound according to any of claims 1 to 8. 13. Use of a compound according to any of claims 1 to 8, characterized in that it is used for the preparation of a medicament intended to treat the diseases in which it is desirable to reduce the immunological activity, in particular the autoimmune diseases. 14. Use of a compound according to any of claims 1 to 8 characterized in that it serves for the preparation of a medicament intended to oppose the proliferation of tumor cells. 5. Use of a compound according to claim 1, characterized in that it is used for the preparation of a medicament for the treatment of heart rhythm disorders